The present disclosure generally relates to the field of extracorporeal photochemotherapy.
Extracorporeal photochemotherapy is an autologous cell therapy technique that consists of obtaining a cell suspension rich in mononuclear cells (apheresis or constitution of a buffy coat in line), adding to it a photosensitizing agent such as 8-methoxypsoralen (8-MOP), and then exposing the suspension to UVA radiation. The cells thus modified are then reinjected into the patient.
Over the past few years, extracorporeal photochemotherapy has become an alternative treatment for various diseases, such as cutaneous T-cell lymphoma, autoimmune diseases, and the acute form and steroid-recalcitrant form of graft-versus-host disease.
The 8-MOP used for extracorporeal photochemotherapy is a molecule that is part of the furocoumarin or psoralen family. In particular, it is the active substance from the Ammi majus plant. 8-MOP can be prepared by extraction and isolation from such a plant using organic solvents. But, residual traces of these solvents, that may present a certain toxicity, are found in the final product.
Synthetic processes for obtaining furocoumarins also exist. For example, U.S. Pat. No. 4,130,568 proposes a process for preparing 8-methoxypsoralen from 6-allyl-7-hydroxy-8-methoxycoumarin. First, this starting product undergoes oxidative cyclization in the presence of a catalyst to form 4′,5′-dihydro-furocoumarin, which is then processed with a strong acid to cleave the hydroxy group at position 5′ and induce dehydrogenation to form 8-methoxypsoralen. The disadvantage of this synthesis is the difficulty obtaining the starting product.
U.S. Pat. No. 4,147,703 also proposes a synthetic process for obtaining 8-methoxypsoralen from 6-hydroxy-7-methoxy-1-benzofuran-2(3H)one (A) by reacting it with hydrogen and a noble metal; (B) by reacting the product obtained in step (A) with a mixture of zinc cyanide and hydrochloric acid; (C) by reacting the product obtained in step (B) with dichlorodicyanoquinone in an inert solvent; (D) by reacting the product obtained in step (C) with ethyl cyanoacetate in a polar solvent; and (E) by decarboxylating the product obtained in step (D) to obtain 8-methoxypsoralen.
A process in three steps for preparing furocoumarins substituted in position 8 from 7-hydroxycoumarin is also described in FR Patent Application No. 2,404,641. The process includes (a) reacting 7-hydroxycoumarin with a halogeno-acetal so as to form a coumarin acetal; (b) transforming the coumarin acetal into aldehyde by heating in a diluted solution; and (c) cyclizing the aldehyde in furocoumarin by heating in an alkaline solution. A global yield of 50% is claimed, which remains relatively low.
In the publication Traven, V. F. (2000), Dihydrofurocoumarinones-new useful intermediates for substituted and condensed furocoumarins, Arkivoc, 4, 523-562, furocoumarinone derivatives are obtained from 7-chloroacetoxycoumarin derivatives by an unusual Fries rearrangement carried out at high temperature. A reduction/dehydration or acetylation step is then proposed to obtain psoralen derivatives. However, this synthesis produces many by-products.